Wang Lingbo, Cai Weili, Zhang Wei, Chen Xueying, Dong Wenqian, Tang Dongqi, Zhang Yun, Ji Chunyan, Zhang Mingxiang
Department of Hematology, Qilu Hospital, Shandong University, Jinan, China.
The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Public Health, Qilu Hospital, Shandong University, Jinan, China.
Oncotarget. 2015 Sep 29;6(29):27490-504. doi: 10.18632/oncotarget.4748.
An abnormal expression of poly(ADP-ribose) polymerase 1 (PARP-1) has been described in many tumors. PARP-1 promotes tumorigenesis and cancer progression by acting on different molecular pathways. PARP-1 inhibitors can be used with radiotherapy or chemotherapy to enhance the susceptibility of tumor cells to the treatment. However, the specific mechanism of PARP-1 in acute myeloid leukemia (AML) remains unknown. Our study showed that expression of PARP-1 was upregulated in AML patients. PARP-1 inhibition slowed AML cell proliferation, arrested the cell cycle, induced apoptosis in vitro and improved AML prognosis in vivo. Mechanistically, microarray assay of AML cells with loss of PARP-1 function revealed that the myeloproliferative leukemia virus oncogene (MPL) was significantly downregulated. In human AML samples, MPL expression was increased, and gain-of-function and loss-of-function analysis demonstrated that MPL promoted cell growth. Moreover, PARP-1 and MPL expression were positively correlated in AML samples, and their overexpression was associated with an unfavorable prognosis. Furthermore, PARP-1 and MPL consistently acted on Akt and ERK1/2 pathways, and the anti-proliferative and pro-apoptotic function observed with PARP-1 inhibition were reversed in part via MPL activation upon thrombopoietin stimulation or gene overexpression. These data highlight the important function of PARP-1 in the progression of AML, which suggest PARP-1 as a potential target for AML treatment.
许多肿瘤中都有聚（ADP - 核糖）聚合酶1（PARP - 1）异常表达的报道。PARP - 1通过作用于不同分子途径促进肿瘤发生和癌症进展。PARP - 1抑制剂可与放疗或化疗联合使用，以增强肿瘤细胞对治疗的敏感性。然而，PARP - 1在急性髓系白血病（AML）中的具体机制仍不清楚。我们的研究表明，PARP - 1在AML患者中表达上调。PARP - 1抑制减缓了AML细胞增殖，使细胞周期停滞，在体外诱导细胞凋亡，并在体内改善了AML的预后。机制上，对PARP - 1功能缺失的AML细胞进行微阵列分析发现，骨髓增殖性白血病病毒癌基因（MPL）显著下调。在人类AML样本中，MPL表达增加，功能获得和功能缺失分析表明MPL促进细胞生长。此外，在AML样本中PARP - 1和MPL表达呈正相关，它们的过表达与不良预后相关。此外，PARP - 1和MPL一致作用于Akt和ERK1/2途径，PARP - 1抑制所观察到的抗增殖和促凋亡功能在血小板生成素刺激或基因过表达后部分通过MPL激活而逆转。这些数据突出了PARP - 1在AML进展中的重要作用，提示PARP - 1作为AML治疗的潜在靶点。
